Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells

• Published in: The Journal of immunology (1950) Vol. 175; no. 3; pp. 1551 - 1557
• Main Authors: Caron, Gersende, Duluc, Dorothée, Frémaux, Isabelle, Jeannin, Pascale, David, Catherine, Gascan, Hugues, Delneste, Yves
• Format: Journal Article
• Language: English
• Published: United States 01.08.2005
• Subjects: CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Proliferation - drug effects; Cells, Cultured; Flagellin - metabolism; Flagellin - pharmacology; Humans; Imidazoles - metabolism; Imidazoles - pharmacology; Immunologic Memory - drug effects; Interferon-gamma - biosynthesis; Interleukin-10 - biosynthesis; Interleukin-2 - biosynthesis; Interleukin-8 - biosynthesis; Leukocyte Common Antigens - biosynthesis; Ligands; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Receptors, CCR7; Receptors, Cell Surface - biosynthesis; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, Cell Surface - physiology; Receptors, Chemokine - metabolism; RNA, Messenger - biosynthesis; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Toll-Like Receptor 3; Toll-Like Receptor 4; Toll-Like Receptor 5; Toll-Like Receptor 7; Toll-Like Receptors; Up-Regulation - drug effects; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.3.1551

TLRs are involved in innate cell activation by conserved structures expressed by microorganisms. Human T cells express the mRNA encoding most of TLRs. Therefore, we tested whether some TLR ligands may modulate the function of highly purified human CD4+ T lymphocytes. We report that, in the absence of APCs, flagellin (a TLR5 ligand) and R-848 (a TLR7/8 ligand) synergized with suboptimal concentrations of TCR-dependent (anti-CD3 mAb) or -independent stimuli (anti-CD2 mAbs or IL-2) to up-regulate proliferation and IFN-gamma, IL-8, and IL-10 but not IL-4 production by human CD4+ T cells. No effect of poly(I:C) and LPS, ligands for TLR3 and TLR4, respectively, was detected. We also observed that CD4+CD45RO+ memory T cell responses to TLR ligands were more potent than those observed with CD4+CD45RA+ naive T cells. Moreover, among the memory T cells, CCR7- effector cells were more sensitive to TLR ligands than CCR7+ central memory cells. These data demonstrate for the first time a direct effect of TLR5 and TLR7/8 ligands on human T cells, and highlight an innate arm in T cell functions. They also suggest that some components from invading microorganisms may directly stimulate effector memory T cells located in tissues by up-regulating cytokine and chemokine production.